Quest for Anti-Aging Drugs Transitions from Flaky to Mainstream

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When I give talks on aging research someone usually asks, “When will scientists develop true anti-aging drugs?” My answer has little to do with what’s happening in the lab, though—it’s about politics, perceptions and money.

It has been clear for many years that the rate of aging is malleable in diverse species, and the discovery in 2009 that a drug called rapamycin can extend maximum life span in mice suggested that it’s now technically feasible to develop anti-aging agents that really work as advertised. Unfortunately, I see no commercial interest in doing so.

Before I go into why that is, consider the most compelling reason to pursue anti-aging drugs. It’s not what many think. Aging is the primary risk factor for almost every mortal malady in the developed world, from Alzheimer’s to cancer to heart failure. Thus, the ability to retard aging would enable an unprecedented postponing of everything that goes wrong with our minds and bodies as we get older. If we could do in humans what we’ve now achieved in mice with rapamycin, we might extend our period of midlife vibrancy by perhaps 10 years. According to a RAND Corp. study, anti-aging drugs capable of this modest slowing of our biological clocks would offer a far more cost-effective way to increase the number of years that we collectively spend in good health than would any other potential medical advance its researchers examined. So the goal isn’t immortality or even a great leap in lifespan—it’s to dramatically boost the quality of our lives on the cheap.

But no sane drug executive would dream of proposing to develop an anti-aging drug. That’s partly because the quest to extend life span has always been linked to snake oil. More importantly, there’s no regulatory framework in place to get an official OK to market such drugs—aging simply isn’t regarded in official circles as a condition warranting medical mitigation. And without the ability to sell anti-aging medicines as high-margin prescription drugs, pharmaceutical makers have no incentive to spend the billions of dollars it would take to develop and test them—they’d never recoup their investments.

Vetting putative anti-aging drugs presents a formidable challenge because it would require first devising a way to test whether they really slow human aging. This might be done by showing that they lower the risks of many diseases of aging while shifting various physiological parameters to patterns correlated with great longevity—extraordinarily low blood levels of insulin in middle age are an example. (Trials lasting decades to see whether they really extend lifespan are plainly untenable.) Since drug companies aren’t about to tackle this challenge, making significant progress on it will probably require federal funding.

Prominent advisors to the National Institute on Aging, as well as some of its officials, are enthusiastic about anti-aging drugs’ huge potential to improve public health. In fact, a few years ago the NIA’s founding director, the late Robert N. Butler, joined three visionary gerontologists to urge that the federal government mount a major program to accelerate development of such medicines, including funding for clinical trials and the preclinical research needed to make them feasible.

But the idea of investing taxpayer dollars in such a program has proved a very hard sell. As gerontologist Richard A. Miller once put it, “A president who announces a war on cancer wins political points, but a president who publicly committed the government’s resources to research on extending people’s life span would be deemed certifiable.”

Which gets us to the root problem: Few people—including policymakers and medical experts who advise them—appear to realize that the ability to brake aging is now within our grasp, and that even modestly effective anti-aging drugs promise the biggest gains in public health since the advent of vaccines and antibiotics nearly a century ago. Indeed, I suspect most people still regard aging as an inalterable part of the human condition—a view reinforced by the fact that pharmaceutical companies just say no to anti-aging drug development.

Perhaps more importantly, I’ve found in talking to people about aging science that its implications are widely misunderstood. For instance, anti-aging agents are often pictured as prolonging the period of late-life decline (despite the fact that no intervention that extends life span in animals does that—indeed, there’s some evidence that such interventions can both postpone and compress late-life morbidity. Then there’s the fear that anti-aging drugs will engender crushing Medicare and Social Security costs (despite the fact that rising life expectancy has long been correlated with increasing economic prosperity—health, wealth and longevity are fellow travelers). See here and my book for more on this.) And some people find the very idea of tampering with humankind’s “natural” life span deeply disquieting (even though we’ve been unnaturally extending our lives ever since we started hurling spears at saber-toothed tigers).

Still, I’ve lately noticed some signs that thought leaders are beginning to get it. In stories about a recent Mayo Clinic study in which signs of aging were delayed in mice by deleting their “senescent cells,” a number of reporters duly noted that such research aims to increase health span, the fraction of life spent in good health, not to make us live forever. And recently the Alliance for Aging Research, an advocacy group for studies on aging, launched a “Healthspan Campaign” to boost support for research that would pave the way for anti-aging drug development. Backed by the American Federation for Aging Research and three major gerontology institutes, the campaign includes a research agenda drafted by an international group of gerontologists that has been endorsed so far by over 60 prominent scientists, including four Nobel laureates. (Disclosure: I’ve consulted with the Alliance about the campaign and written a whitepaper for release as part of it.)

Turning the formerly flaky anti-aging quest into a mainstream medical enterprise will take time, and for graying boomers like me the benefits may arrive too late. But I can’t think of a better gift my generation could present to our kids than the very real prospect of astoundingly healthy aging.

16 Comments

Thank you for this insightful post, David. I have heard some open-minded folks describe aging as simply another disease we face as humans, and I wonder what your opinion is on this notion that aging is just a disease occurring on a cellular level. Thanks, and happy holidays.

David Stipp is correct in predicting that aging will be a realm for increasing attention from researchers. However, his optimism for quick results may be unfounded. He cites very iffy reasons to expect this to be easy.

Yes, it has proved possible to alter and extend the mean lifespans of study populations of flies and mice through various means. Rapamycin is one such trigger. Other researchers have achieved notable results by delaying sex and reproduction and/or via caloric restriction – limiting test subjects to nutritious but very-spare diets.

So far, alas, scattered attempts by human beings to emulate all this – (by limiting themselves to ascetic lifestyles) – have shown little or no appreciable anti-aging effects. (And some have been trying the experiment on themselves for decades.) I’ll be very surprised if those impulsive folks now dosing themselves with rapamycin will achieve anything, either.

Think. For at least 4000 years there have been ascetic monastic communities that would have stumbled, by now, into any “thin-diet” approach for 200 year lifespans.

Elsewhere, I’ve gone into about a dozen reasons why our search for youth elixers will be hard and grindingly slow. Human beings are very different from mice, or even apes, for reasons that may surprise you. http://www.davidbrin.com/immortality.htm

Essentially it’s this. We have already plucked all the low-hanging fruit. We are already the methuselahs of mammals, getting THREE TIMES the usual number of heartbeats. The mouse results consist largely of making them (the mice) be more like us. It is going to be a lot harder to go the other direction. To make us humans more like gods.

David Brin, Ph.D
uthor of The Postman and Earth and The Transparent Society: Will Technology Make Us Choose Between Privacy and Freedom?http://www.davidbrin.com

When will science be able to control population levels so that longer living individuals won’t simply be diminishing the resources available and the quality of life for the larger majority of individuals?

Excellent article, but I wanted to add something else from the perspective of the pharmaceutical industry. We make our money not off “curing” disease, but lessening the symptoms. It’s comparable to having two choices of a new big screen HDTV (just an example): Buy it and own it completely for $100,000 . . . or have it in your house and pay it off $60 per month. We make more money off the latter. What was the last actual “cure”? Polio? Dementia, Arthritis, all of those diseases are “symptoms” or aging. We apparently realized years ago that we will make trillions of dollars over time nursing you through the symptoms rather than curing the disease. Think of the “blockbuster” drugs out there and what diseases they address: Lipitor, Diovan, etc.- they are for hypertension, diabetes, all of the symptoms of aging. It’s really a travesty to mankind, but we all should know by now that money trumps everything.

an effective anti-aging drug would be the mother of all blockbuster drugs. Unlike other medications it would not be applicable to just a subset of humans but to ALL humans. So there’s no reason to believe the pharmaceutical industry would avoid trying to develop such a drug if there was sufficient reason to believe it was possible.

Studies suggest that cellular senescence is a process actively mediated by the products of genes such as p16ink4a which “shut down” stem cell proliferation as the organism ages. Knockout mice which lack p16ink4a appear to be more youthful than their normal counterparts but also die early of tumors, suggesting that there is no free lunch: i.e., anything which retards aging by preventing the loss of stem cells will increase the risk of cancer via the same mechanism. In other words, there may be a tradeoff between preventing cancer by shutting down stem cell proliferation versus aging. It would be ironic if humans taking anti-aging drugs are forced to spend most of their extended days in oncologists’ offices.

In response to jdthejd: I don’t like to apply the word “disease” to normal aging, though I know some gerontologists who do. This is partly due to a semantic reason: I think of “disease” as applying to subsets of the population, while the word aging means something that hits everyone. Also, I think calling “aging” a disease makes it sound as if it might be curable in the forseeable future — which I don’t think it will be. I regard talk of attaining a permanently youthful state as an interactive fantasy genre, like aeronautical engineers bandying about ideas for faster-than-light spaceships. My view on this is partly based on the fact that I’ve covered the drug/biotech industries for decades as a reporter and have watched how extraordinarily hard it is make even incremental progress against a single disease of aging like cancer or Alzheimer’s — biology is dauntingly complex and full of surprises.

In response to David Brin: I agree that it will be hard to slow aging — rather than expressing optimism for “quick results,” as you assert, I mentioned that the payoffs from research on ways to the rate of aging may arrive too late to benefit “graying boomers like me,” meaning that success is likely to require many years of further work. Further, I’ve never suggested in this forum or anywhere else that youth elixirs capable of conferring 200-year lifespans are in the offing, as you imply. Rather, I’ve echoed prominent gerontologists, including Robert Butler and Richard A. Miller, who have argued that it will probably be possible in the foreseeable future (based on advances such as the work on TOR) to “modestly decelerate” aging enough to increase healthy life expectancy by perhaps 5-10 years. I think this is doable, and it would represent a huge gain. (How huge?–Consider that we now routinely spend something like one to two billion dollars over a couple of decades to develop a drug that increases life expectancy of patients with a single form of cancer by a few months.) We know human lifespan can reach 115+, and “supercentenarians” who live that long tend to remain in extraordinarily good shape through their 90s and beyond. Thus, it’s arguable that our species’ typical healthspans and lifespans might be further optimized by something like 50% if we could emulate the effects of the genetic, or perhaps epigenetic, factors that are largely responsible for the rare extremely long, healthy lives that are on record. And we’re beginning to get a handle on what they are via studies on human centenarians and animal gerontogenes, though there’s still a long way to go. Again, I’m not arguing that we’ll soon find drugs that increase average healthy life by 50%. But I agree with gerontologists who argue that about a 10% gain now appears to be technically feasible based on what’s happening in the lab.

In response to jtdwyer: I don’t think modestly increasing healthy lifespan, which is what I’m talking about, would have much effect on the world population versus huge demographic trends such as the baby bust. (See Longman’s piece in Foreign Affairs on that, if you’re interested in the unfolding bust.) Besides, lifestyle trumps raw population figures–sustainability is affected much more at this point by factors such as the average size of carbon footprints than the number of footprints (e.g., U.S. energy use per capita is more than twice that of Europe’s). And healthier aging would help, not hurt, economic prosperity, freeing up resources to devote to fixing the U.S. energy infrastructure so it releases less carbon into the atmosphere.

In response to bigbopper: I used to think that there was a nearly inevitable tradeoff between the risk of cancer and the pro-aging effects of cellular senescence. But the recent Mayo Clinic mouse study in which p16ink4a-expressing senescent cells were simply deleted as they formed has changed my view on this — it seems from this study that there’s hope to suppress the deleterious effects of cellular senescence without necessarily increasing the risk of cancer, though more work is needed to clearly prove that, if it’s the case.

In response to the comments from David Stipp and others, and the article, I have two questions:

1. I understand the skepticism for finding a way to alter metabolism to be significantly (more than 10% or so) less damaging. It makes sense that evolution has already picked the low hanging fruit. But what about Aubrey de Grey’s proposal to categorically eliminate the damage in each specific form after it occurs, using mechanisms that couldn’t plausibly evolve on their own? Is this somehow considered *less* plausible on a scientific level, or are you only omitting it to keep the signal to noise ratio down? (The same question applies to David Brin’s article.)

2. At the risk of opening a yet bigger and scarier can of worms… why isn’t cryonics (what cryobiologist Brian Wowk has described as “Medical Time Travel”) taken more seriously by greying boomers who are skeptical of the development of antiaging cures in their lifetimes? Has a proposal never been seriously entertained to devote a large amount of public funding to preventing damage to the clinically dead (and terminally ill) during the inducement of cryogenic stasis? Even assuming contemporary cryonics is utterly hopeless, why wouldn’t there be more attention given to improving the process?

Speculating is easy, data is hard, actually extending healthy lifespan in mammals a reproducible way is extremely rare. I’m interested in the hard and rare, not futuristic speculation about ways to achieve immortality, though I have to admit it makes for great headlines in newspapers and magazines. At this point, cryonics visionaries are basically sci-fi authors–there are only 13 articles/papers mentioning the term cryonics listed in Pubmed, the National Library of Medicine’s online site, and they have appeared in places like Bioethics and the New Yorker, not Nature and Science. Aubrey de Grey has some interesting ideas. But the scientists I regard as knowing the most about aging–gerontologists who have spent their careers doing hard experiments with living organisms–don’t appear to find them very plausible. See, for example, http://www-personal.umich.edu/~millerr/FlyPigs.htm

You might try some different search terms on the topic of cryonics if that’s your actual objection. I would suggest “vitrification”. There is no speculation on, for example, the matter of whether you can vitrify a whole rabbit kidney and reanimate it with adequate function to keep the animal alive.

I do agree that cryonics is speculative in some respects. We do not know whether enough brain tissue structure can be preserved, and of course we don’t know if we can (or can’t) engineer our way to preserving well enough them within our lifetimes. We won’t have access to that data for many years, unless we somehow achieve an exceptionally early breakthrough. I have a hard time understanding why anyone expects it to be any different, let alone why they would consider this a valid counterargument.

As to Miller’s dismissal of Aubrey de Grey, I regret to say did not find his analogy to flying pigs compelling. However he did link to an article explaining his skepticism more seriously. http://www.ncbi.nlm.nih.gov/pubmed/16264422 It seemed to be based mainly on the fact that Aubrey is overselling particular points that should be left to empirical experiments. What got me about it was that the authors didn’t seem to appreciate, let alone refute, the engineering paradigm.

For example they apparently multiplied the probabilities of all seven proposed strategies to get their probability of the proposal as a whole being a success. That to me seems disingenuous, as the proposal as a whole is deliberately comprised of modular parts — you would logically test the most likely seeming version of each part and if one doesn’t work you swap it out with something that works. What would be interesting (to the point of perhaps demanding a modification to the proposal) would be to demonstrate that one is dependent on another in some way that de Grey has failed to mention. But to the extent that it is modular, with the individual parts being subject to replacement, the proposal is much more robust than these mainstream gerontologists seem willing to admit.

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